Efficacy and Safety of TAK-653 in Treatment-Resistant Depression

A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of TAK-653 in the Treatment of Subjects With Treatment-Resistant Depression

The purpose of this study is to evaluate the efficacy of TAK-653 compared with placebo in maintaining the effect of ketamine treatment on depressive symptoms.

The drug being tested in this study is called TAK-653. TAK-653 is being tested to treat people who have depression and have not responded to several treatments (treatment-resistant depression).

This study will look at the efficacy and safety of TAK-653 in participants with treatment-resistant depression who take TAK-653 in addition to standard care.

The study will enroll approximately 90 patients. Participants who meet the study entry criteria will be assessed for response to ketamine by administering 2 intravenous (IV) infusions of ketamine (0.5 mg/kg given over 40 minutes; maximum dose 40 mg/day) on Day -5 (±1) and Day -1 (±1). To determine response to ketamine, the Day -5 predose Montgomery Åsberg Depression Rating Scale (MADRS) total score (before the first ketamine infusion) will be compared with the MADRS total score predose on Day 1 (24 hours after the second ketamine infusion on Day -1). Two cohorts (ketamine responders and ketamine nonresponders) of participants will be enrolled in parallel into the study.

Participants will then be randomly assigned (by chance, like flipping a coin) to one of the two treatment groups - which will remain undisclosed to the participant and study doctor during the study (unless there is an urgent medical need):

• TAK-653
• Placebo (dummy inactive pill) - this is a tablet that looks like the study drug but has no active ingredient.

All participants will be asked to take one tablet at the same time each day throughout the study. This multi-center trial will be conducted worldwide. The overall time to participate in this study is 78 days. Participants will make multiple visits to the clinic, and will be contacted by telephone on Day 78 after last dose of study drug for a follow-up assessment.

Inclusion Criteria:

1. Has a primary diagnosis of major depressive disorder (MDD), without psychotic features, according to Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM 5) criteria, as assessed by a board-certified psychiatrist. MDD should be the principal diagnosis and the condition that best accounts for the clinical presentation. Participants with a secondary diagnosis of generalized anxiety disorder or social anxiety disorder may be included if, in the principal investigator's judgment, such diagnosis will not interfere with participation in the study or with outcome assessments. The diagnostic assessment must include a face-to-face evaluation of the participant using the Mini International Neuropsychiatric Interview (MINI).
2. Has MDD that is resistant to treatment (i.e., TRD), defined as failure to respond to at least 2, but not more than 5, adequate trials of pharmacological treatment in the current episode, as determined using the Massachusetts General Hospital - Antidepressant Treatment Response Questionnaire (MGH ATRQ).
3. Qualifies as a candidate for receiving ketamine infusions as a treatment for their depression, in the opinion of the investigator.
4. Is naive to ketamine treatment.
5. Has a Hamilton Depression Rating Scale-17 (HAMD-17) total score of ≥22 at Screening.
6. Is on stable pharmacological treatment for depression (≤50% change in dose) during the last 6 weeks prior to Randomization. Participants who are not currently taking pharmacological treatment for depression may be eligible, with the approval of the medical monitor.

Exclusion Criteria:

1. The participant or any immediate family member has a seizure disorder or a history of seizure disorder, except febrile convulsions.
2. Is currently diagnosed with a personality disorder, dementia, eating disorder, schizophrenia, schizoaffective disorder, or bipolar disorder.
3. Has a history of neurological abnormalities that is judged by the medical monitor to preclude the participant's participation in the study; or brain injury including traumatic injury, perinatal encephalopathy, and postnatal brain damage, blood-brain barrier abnormality, and cavernous angioma.
4. Has a history of cerebral arteriosclerosis.
5. Is currently diagnosed with glaucoma.
6. Is at an imminent risk of suicide per the Columbia - Suicide Severity Rating Scale (C-SSRS) (score of 5) or per the investigator's clinical judgment.
7. Has uncontrolled hypertension or a systolic blood pressure of >150 millimeter of mercury (mm Hg) or diastolic blood pressure >95 mm Hg at Screening.
8. Has a positive urine test result for drugs of abuse (defined as any illicit drug use) at Screening or Day 1.
9. Has a blood alcohol content of ≥0.06% at Screening, prior to ketamine infusion (Day -5 or Day -1), or Day 1.
10. Is currently diagnosed with abuse of or dependence on alcohol or other drugs (except nicotine). The participant will be allowed to enroll if his/her drug and alcohol abuse/dependence is in full (complete, not partial) sustained (>1 year) remission.
11. Has any contraindication to the administration of ketamine.